This invention relates to an improved stereospecific process for producing azetidinones useful as hypocholesterolemic agents and as intermediates for the synthesis of penems.
In a process heretofore utilized to prepare azetidinones, a boron enolate of a butyrimide, prepared from butyric acid and 4(R),5(S)-4-methyl-5-phenyloxazolid in one, and 3-methoxymethylphenyl-acetaldehyde are reacted to form a compound of formula ##STR2## as disclosed in Evans, et al, Tetrahedron Letters, 27 (27), 3119-3122 (1986). The chiral oxazolidinone is displaced by reacting with methoxyamine hydrochloride and trimethylaluminum to form a .beta.-hydroxyhydroxamide. The .beta.-hydroxy group is converted to a mesylate, which is cyclized by treatment with potassium carbonate to form an N-methoxyazetidinone. Finally, the N-methoxyazetidinone is reduced by dissolving metal reduction, using lithium and ammonia, to form an azetidinone of formula ##STR3##
Gage, et al, Organic Synthesis, 68, 77-91 (1989) discloses a process for preparing (2S*,3S*)-3-hydroxy-3-phenyl-2-methyl-propanoic acid from a chiral oxazolidinone. The process is shown in Reaction Scheme I. ##STR4##
Jung, et al, Tetrahedron Letters, 26 (8), 977-980 (1985), disclose a process for converting a .beta.-hydroxy-carboxylic acid to an N-hydroxy-.beta.-lactam. The process is shown in Reaction Scheme II. In addition, Jung, et al incorporate by reference Mattingly, et al, J. Amer. Chem. Soc., 101, 3983 (1979) and Miller, et al, J. Amer. Chem. Soc., 102, 7026 (1980) which disclose methods for the reductive cleavage of N-hydroxy-.beta.-lactams to form .beta.-lactams. ##STR5##
The Evans, et al, process suffers from several shortcomings. In particular, the process has not proved applicable to all azetidinones of formula I, below. With some substrates, the use of trimethylaluminum to form the .beta.-hydroxy-hydroxamide results in a low reaction yield and requires laborious purification procedures to isolate the product. In addition, where the Evans, et al. process is used for preparing compounds of formula I, wherein --A--R.sup.1 (as defined below) is capable of stabilizing a carbo-cation, e.g. wherein --A--R.sup.1 is phenyl, naphthyl or W-substituted phenyl or naphthyl, the mesylate cyclization step is accompanied by epimerization.
The process of Gage, et al, provides an efficient route to .beta.-hydroxy-carboxylic acids. However, the Jung, et al, process for converting such compounds to .beta.-lactams suffers from a lack of generality, giving variable yields of product in the cyclization step, depending upon the substrate employed.